Drug Combinations Prove Effective Against Melanoma Brain Metastases

STUDIES PRESENTED at the 2017 ASCO Annual Meeting have shown that for melanoma that metastasizes to the brain, the combined use of checkpoint inhibitors and targeted agents can be effective.

In COMBI-MB, 58% of patients responded intracranially to the BRAF inhibitor dabrafenib (Tafinlar) plus the MEK inhibitor trametinib (Mekinist).1 In CheckMate 2042 and the Australian Anti–PD-1 (programmed cell death protein 1) Brain Collaboration (ABC) trials,3 the combined use of nivolumab (Opdivo) plus ipilimumab (Yervoy) yielded intracranial response rates of 55% and 42%, respectively (Table 1, bottom of web page). These are new and important findings, according to the studies’ investigators.

Michael A. Davies, MD, PhD

“Metastatic melanoma has a high risk of spreading to the central nervous system (CNS). Brain metastases are observed in 43% of patients in clinical studies and in 75% of autopsies,” said Michael A. Davies, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston. “Patients with active brain metastases have typically been excluded from most large melanoma trials to date. Treatment of melanoma brain metastases remains a critical unmet medical need in this disease.”

COMBI-MB: Dabrafenib and Trametinib

COMBI-MB evaluated dabrafenib at 150 mg twice daily plus trametinib at 2 mg/d in 125 patients with BRAF mutations and brain metastases not previously treated with a BRAF or MEK inhibitor. Patients were stratified into four cohorts based on specific mutation, presence or absence of symptoms, performance status, and whether local therapy was previously administered.

Intracranial responses were observed in 44% to 59% of patients, depending on the cohort, and intracranial disease control rates ranged from 75% to 88%. Five patients in the study achieved complete responses, Dr. Davies reported.

Extracranial responses were observed in 41% to 75% of patients, and extracranial disease control was achieved in 65% to 94%. The median duration of intracranial response ranged from 4.5 to 8.3 months.

The primary endpoint was intracranial response in patients with a BRAF V600E mutation; asymptomatic with a good performance status; and without prior CNS-directed local therapy, who comprised the study’s largest cohort (76 patients). The primary endpoint was met, with 58% of patients responding to dual inhibition.

TREATMENT OF MELANOMA BRAIN METASTASES

Brain metastases are common in advanced melanoma, and most clinical trials have excluded such patients.

Three key melanoma trials found that combinations of checkpoint inhibitors and of BRAF/MEK inhibitors can effectively
treat brain metastases.

Intracranial responses were achieved by 58% of patients receiving dabrafenib plus trametinib in COMBI-MB; by 55% of patients receiving nivolumab plus ipilimumab in CheckMate 204; and by 42% of patients receiving nivolumab plus ipilimumab in the ABC trial.

Among these 76 patients, median progression-free survival was 5.6 months, and 6-month and 12-month progression-free survival rates were 44% and 19%, respectively. Median preliminary overall survival for this cohort was 10.8 months, and 46% of patients were alive at 12 months, he said.

“This is the first report of a phase II trial evaluating a BRAF inhibitor and MEK inhibitor in patients with melanoma brain metastases,” he noted. “The results support the use of this combination as a treatment option for melanoma patients with brain metastases—but also the need for continued research to further improve outcomes.”

“In patients with advanced melanoma and untreated brain metastases, nivolumab plus ipilimumab demonstrated clinically meaningful efficacy. We believe that this can become a new treatment option,” Dr. Tawbi said.

Hussein Tawbi, MD, PhD

CheckMate 204 enrolled melanoma patients with at least one unirradiated brain lesion (0.5–3.0 cm) and no prior treatment with a checkpoint inhibitor. Prior stereotactic radiotherapy was allowed for three or fewer lesions, as was prior targeted therapy.

The objective response rate was 53% for the global assessment, 55% for intracranial disease, and 49% for extracranial disease. Intracranial complete responses were observed in 16 (21%) of the 75 patients. Median duration of response was not reached, and 38 (93%) of 41 responders had responses ongoing for at least 6 months, he reported.

At 6 months, the progression-free survival rate was 67%, and median progression-free survival was not yet reached. “Patients appear stable out to 9 months. The plateau of the curve is promising,” Dr. Tawbi commented.

The study is now enrolling a cohort of patients who are symptomatic and/or require steroids.

Georgina V. Long, BSc, PhD, MBBS

ABC (Anti–PD-1 Brain Collaboration) Results

THE PHASE II ABC trial assigned treatment based on prior therapy. None of the patients could have had immunotherapy, but previous targeted therapy was allowed. Patients in cohort A (n = 33) had no prior local therapy, were asymptomatic, and received nivolumab plus ipilimumab, the same as in CheckMate 204. Cohort B patients (n = 27) had no prior therapy, were asymptomatic, and received only nivolumab. Cohort C patients (n = 16) were previously treated and were symptomatic or had leptomeningeal disease, with progression on magnetic resonance imaging, and received only nivolumab. This arm was ultimately suspended.

Based on the high level of activity observed in the ABC trial for the combination, Georgina V. Long, BSc, PhD, MBBS, of Melanoma Institute Australia, University of Sydney, agreed with CheckPoint 204 investigators that “nivolumab combined with ipilimumab may be considered for upfront therapy” in patients with active asymptomatic melanoma brain metastases who have not had local therapy.

“The response rate is high when nivolumab plus ipilimumab is given upfront.”

— Georgina V. Long, BSc, PhD, MBBS

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The intracranial response rate with the combination was 42%, and 46% of patients were progression-free at 6 months, compared to 20% and 29%, respectively, for the nivolumab-alone groups, Dr. Long reported. “The response rate is high when nivolumab plus ipilimumab is given upfront,” she added. In patients with no prior BRAF or MEK inhibitor therapy, the intracranial response rate was 50%, compared to 16% for patients with previous targeted treatment. This may be informative in terms of sequencing treatments in the future, Dr. Long said.

At 1 year, all complete responders were alive, as were 90% of partial responders and about 45% of patients with stable disease. None of the patients with progressive disease as best response were alive at 4 months.

The extracranial response rate was 48% with the combination and 30% with the single agent. Median extracranial progression-free survival was 5.3 months and 2.7 months, respectively.

“Intracranial and extracranial responses were mostly concordant,” Dr. Long noted.

The researchers will be evaluating the addition of radiotherapy to nivolumab plus ipilimumab in patients whose best response is progressive disease in the brain.

Safety Profile

NO NEW SAFETY signals emerged in these studies. In COMBI-MB, 48% of patients experienced a grade 3/4 adverse event, with 10% of patients discontinuing because of toxicity. In CheckMate 204, grade 3/4 adverse events occurred in 52%, the highest frequency being gastrointestinal (13%); 31% discontinued treatment due to an adverse event, and 1 patient died of treatment-related myocarditis. In the ABC trial, 46% of patients had a grade 3/4 treatment-related adverse event, and 27% discontinued treatment due to toxicity. ■

TABLE 1: Intracranial Response to Treatment

Trial

Agents tested

Intracranial disease control rate*

6-month progression-free survival

COMBI-MB (N = 125)

Dabrafenib plus trametinib

75%–88%

31%–71%

CheckMate 204 (N = 75)

Nivolumab plus ipilimumab

60%

67%

ABC (N = 75)

Nivolumab plus ipilimumab vs nivolumab

Nivolumab plus ipilimumab: 50% Nivolumab: 24%

62% 53%

DISCLOSURE: Dr. Davies has had a consulting or advisory role with Genentech/ Roche, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, Sanofi, and Vaccinex and has received institutional research funding from AstraZeneca, Genentech/Roche, GlaxoSmithKline, Merck, Myriad Genetics, Oncothyreon, and Sanofi. Dr. Tawbi has had a consulting/advisory role for Novartis. Dr. Long has received honoraria from Bristol-Myers Squibb, Merck, and Roche; has consulted or advised for Amgen, Array BioPharma, Bristol-Myers Squibb, Merck, Novartis, Pierre Fabre, and Roche/Genentech; and has received travel expenses from Merck and Roche/Genentech.

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